This proposal is designed to investigate the mechanisms by which normal body temperature regulation is altered when man or animals become infected by pathogens that cause a cardinal sign of disease - fever. It will examine in detail the manner by which endogenous pyrogen acts upon the central nervous system to produce fever. Based upon results obtained from previous research supported by this grant, a hypothesis on the nature and site of action of endogenous pyrogen at the blood-brain interface is presented. The model proposed contains both anatomical and physiological elements that can account for the sequence of events that occurs from when endogenous pyrogen is released from mononuclear cells in the circulation until body temperature rises. Several experimental protocols are described that will test directly the validity of this hypothesis. A study of the hypothesized site of release of prostaglandins is proposed, leading to an examination of the properties of neurons located in the periventricular region of the hypothalamus that may be responsible for fever production. Methods are described for the exposure, recording and marking of cells, in order to investigate the connectivity of individual neurons in this region to other CNS centers believed to be involved in thermoregulation.